Prostate cancer is characterized by large genomic rearrangements and deletions. We show that the genes CHD1 and MAP3K7 are co-deleted in ERG translocation negative prostate cancer. To demonstrate a functional cooperativity we used a novel mouse prostate stem cell developmental model and showed that collaborative loss of CHD1 and MAP3K7 promotes an aggressive prostate cancer phenotype with altered lineage differentiation, abnormal secretory products, massive nuclear atypia, loss of E-cadherin and enrichment in neuronal and neuroendocrine markers. Profound alterations in AR expression were also observed. Using a LNCaP model we also demonstrate that loss of CHD1 and MAP3K7 promotes castrate-resistant prostate cancer. The functional interactions of other copy number alterations with the aggressive CHD1/MAP3K7 null phenotype will be explored in Aim 1. Aim 2 will define the functional roles of androgen receptor variants and downstream targets in a castration model of prostate cancer and identify novel mediators of aggressive growth. We have validated immunohistochemical techniques to detect loss of protein expression in clinical specimens. In Aim 3 we will assess the prognostic value of immunohistochemistry in prostate tissue from a unique cohort of men with robust clinical outcomes. This work could have impact on the management of the most aggressive prostate cancer. Co-deletion of CHD1 and MAP3K7 occurs in 10-15 % of primary tumors. Relapse occurs in approximately 50% of patients with co-deletion. If these deletions occur in primary tumors and predict poor survival, men could be stratified based on MAP3K7 and CHD1 status. A functional understanding of this variant of prostate cancer could lead to novel therapeutic targeting strategies in the future.